In recent years, the cancer mortality has become the first leading cause of death in China, that was probably related to smoke, the population aging, the industrialization process, etc. The incidence of common tumors such as esophageal cancer, stomach cancer, liver cancer and so on has remained in a constant high level in traditional poor zones, while the incidence of lung cancer, breast cancer, colonic cancer and so on has already fast increased in rich countries. The latest investigation indicated the incidence of brain neoplasm in developed countries was rising, and this disease further showed an evident low aging tendency, and gradually approached young people under 40 years-old, and became one of important tumors threatening children health. According to U.S. statistics, as far as the tumor death causes in 20˜40 years-old people, brain neoplasm is the first leading cause in men, and the fifth leading cause in women, indicating the great harmfulness of brain neoplasm to public society. Nowadays, brain neoplasm is still one of first mortality cancers in adults, while is the solid tumor with highest incidence in children.
Neuroglioma, also called gliocytoma, is a common malignant tumor occurred in central nervous system, and arises from neuroepithelium and accounts for 40%˜50% of all intracranial neoplasmas, which is characterized by high incidence rate, high recurrence rate, high fatality rate and low recovery rate. Based on the cell differentiation of glioma, glioma can be classified as astrocytoma, oligodendroglioma, ependymoma, etc, and its growth feature is infiltrative, without obvious margin with normal brain tissue. In general, its growth does not limit to one lobe of brain, and penetrates from inside brain tissues to the outside in finger-like shape, destroying brain tissues. At present, the main therapeutic measure for brain glioma is surgical ablation, but the 5-year survival rate is low. Glioma is not sensitive to radiotherapy and chemotherapy, thus, there is an urgent need for development of biological drugs used for its therapy.
There are many methods for classification of brain neoplasms, and currently, unified classification cannot be found. Moreover, histogenesis and pathologic characterization of various neoplasms are different, and their benign and malignancy as well as biological perperties are further not same. Astrocytoma, oligodendroglioma, and ependymoma differ from each other in many ways, and the specific difference is as follows:
1. Astrocytic tumor is a glioma consisted with astroglia cells, and as a most common refractory tumor, it accounts for 13%˜26% of intracranial neoplasms and 21.2%˜51.6% of neuroepithelial neoplasms. In gliomas, glioblastoma is the most common primary brain tumor, and the median survival of patients is merely about 15 months. Gelatinous membrane cell tumor shows invasive growth, and may extensively infiltrate into normal brain tissues, resulting in difficulty in surgical ablation; next, glioblastoma is resistant to general radiotherapy and chemotherapy, that is the important reason that it has high fatality rate and high recurrence rate. For its pathogenesis has not been fully interpreted, currently, effective therapeutic methods of brain glioblastoma is absent. Astrocytoma and oligodendroglioma are different in the expression level of RTN4. Expression of RTN4A in oligodendroglioma is obviously higher than that in astrocytoma, that is used for identifying the specificity and the sensitivity of oligodendroglioma.
2. Oligodendroglioma is a rarer neuroepithelium cancer, and usually found in adults, with an average age of onset being about 40 years old. In the past, due to limitation of examining techniques and pathological diagnosis level, it is easy for oligodendroglial tumor to escape diagnosis or be misdiagnosed, and literature indicates it accounts for 2%˜5% of primary intracranial tumors, and 2%˜12% of brain gliomas. But, in recent years, with the constant development of clinical research and the constant improvement of pathological diagnosis level, the detection rates of oligodendroglioma obviously increase, and literature reports it occupies about 33% of intracranial gliomas. Oligodendroglioma is an intracranial tumor arising from oligodendrocytes, and as an independent type of glioma, it accounts for 4.39% of intracranial tumors. In recent years, a great advance has been made in study on molecular genetics of oligodendroglioma, and the most common genetic change is the loss of heterozygosity on long arm of chromosome 19, while the second common genetic change is the loss of heterozygosity on short arm of chromosome 1. According to WHO newest classification of pathologic grading (2007), oligodendroglioma is classified as simple-type oligodendroglioma and mixed-type oligodendrocyte astrocytoma. The simple-type oligodendroglioma is further classified as low grade oligodendroglioma (Grade II), high grade oligodendroglioma (Grade III), and multiform glioblastoma (Grade IV); mixed-type oligodendrocyte astrocytoma is further classified as oligodendrocyte astrocytoma (Grade II) and anaplastic astrocytomas (Grade III). Recent investigation indicates low grade of oligodendrocyte tumors are more sensitive to chemotherapy, and different grade of oligodendrocyte tumors have obvious different clinical outcome and prognosis.
3. Ependymoma is a central nervous system neoplasm arising from ependymal cells in cerebral ventricles and spinal canal or ependyma cell nests of cerebral white matter. It accounts for 18.2% of gliomas, and is commonly seen in children and young, men much more than women. About 75% of ependymomasare below the tentorium, while 25% are above the tentorium. This tumor is extensively seen in cerebral ventricles, and a small number of tumor body in brain tissues. Ependymoma is a neuroepithelial neoplasm originating from ependymal epithelium cells, and may occur in intracalvarium and in spinal canal. It may spread along subarachnoid space, and at present, it is hard to completely cure it. Different pathologic types of gliomas have their respective high risk ages, and the high risk age of ependymoma is 10 years-old. Based on foreign statistics, 96% of ependymomasare seen in adults, and the high risk age is about 35˜45 years-old. It is a most-common spinal cord neoplasm in adults, and about accounts for 34.5% of all ependymomas of central nervous system and 60% of intramedullary tumors and 75% of ependymomas in adults. Investigation has shown that for ependymomas, 50% of them lost the segment of chromosome 22, and that gene SV40 is closely related with ependymoma. According to the newest classification, ependymal tumors are classified as: (1) ependymoma: having four subtypes: {circle around (1)} cellular type; {circle around (2)} papillary type; {circle around (3)} clear cell type; {circle around (4)} tanycyte type. (2) anaplasia or malignant ependymoma: tumor cells are densely packed, with morphologically distinct cells and nucleus, as well as visible mitotic figures and necrosis areas. (3) myxo-papillary ependymoma: tumor cells are arranged in papillary shape, and connective tissues surrounding papillary structures have mucoid-appearing changes. (4) sub-ependymoma: most cells forming tumors are sub-ependymagliacytes, with visible pseudorosettes arrangement. Small amounts of ependymal cells and ependyma mother cells are sometimes distributed among gelatinous fibers. Ependymal tumors are not sensitive to chemotherapy, and in clinical trials, when various chemotherapeutic agents are administrated alone or together, the effect is weak.
Treatment of glioma is mainly by surgery, but for poor cell differentiation, rapid proliferation, strong invasiveness, current operation manner cannot completely remove tumors, and a combined modality therapy is generally accepted. Post operation radiotherapy and chemotherapy are the received therapeutic method, however, the radiation tolerance of tumor cells to radiotherapy probably causes the further recurrence of residual lesions. In addition, brain tumors are all not so reactive to chemotherapy, and one of reasons is that only a few drugs can pass through the blood-brain barrier. Because of blood-brain barrier, higher hydrostatic pressure of brain tissue spaces caused by edema of tumor tissues and their periphery, as well as other factors, the effective concentration of chemotherapeutic drugs in tumors is lower. Further, development of drug tolerance of tumors, adverse reaction of systemic administration and so on all have an effect on treatment effectiveness of chemotherapy. In order to improve therapeutic effect of gliomas, from molecular pathogenesis of glioma to new clinical therapeutic tools, people have done lots of work.
Chlorogenic acid widely exists in various medicinal plants, such as Flos Lonicerae, and nowadays, its structure has already been determined. Its medicinal uses have been investigated, and it is reported that chlorogenic acid can treat tumors and other diseases. At present, literature reporting that chlorogenic acid is used for treatment of glioblastoma mainly focuses on mechanism of action, such as reference “The chemopreventive properties of chlorogenic acid reveal a potential new role for the microsomal glucose-6-phosphate translocase in brain tumor progression” reports glucose-6-phosphotransferase (G6PT) in brain glioma cell lines U87 can regulate intra-cellular signaling pathway, and presents high expression state, that is closely related to invasion of tumor cells; chlorogenic acid can antagonize U87 cell migration induced by G6PT, and obviously inhibit U87 cell migration induced by sphingosine (SIP). It is proved that chlorogenic acid can achieve effects of inhibiting neoplasm metastasis by inhibiting activities of matrix metalloproteinase and glucose-6-phosphotransferase. Reference “Inhibition of MMP-2 secretion from brain tumor cells suggests chemopreventive properties of a furanocoumarin glycoside and of chalcones isolated from the twigs of Dorstenia turbinata” reports chlorogenic acid, as inhibitor of matrix metalloprotein transferase, can inhibit secretion of MMP-2, and realize to inhibit cell transfer of glioblastoma of brain tumors. Chlorogenic acid is an inhibitor of G6PT. That indirectly indicates effects of chlorogenic acid on brain neoplasms. But, G6PT mentioned in literature is a generalized carcinogen, and referred brain neoplasms are also a broad definition, that cannot show direct effects of chlorogenic acid on brain tumors. Le Wang (Extraction, isolation and purification of chlorogenic acid from Acer truncatum, Northwest University, Master's thesis 20100401) reports anticancer and anti-aging actions of chlorogenic acid, which discloses chlorogenic acid can inhibit metastasis of glioma as well as secretion of metallothionein (MMP) in human Hep3Bhepatoma carcinoma cells, and has significant therapeutic effects on large intestine cancer, liver cancer, and larynx cancer, thus it is regarded as an effective protective agent against cancers.
In summary, effects of chlorogenic acid on brain tumors reported by literature limit to glioblastoma, one type of astrocytomas (explaining in “mechanism of action”), without in vivo pharmacodynamic test verifying the use of chlorogenic acid for treatment of brain glioblastoma, as well as without related reports about the inhibitory action of chlorogenic acid on brain glioma stem cells.